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The aim of this study is to assess benefits of treatment with intravenous Curcumin® (CUC-01) vs placebo, in combination with paclitaxel chemotherapy, and to estimate the risk of adverse events in patients with locally advanced and metastatic breast cancer.
This is a randomized, double-blind, placebo-controlled, two arms parallel group phase 2 clinical trial:
Group A, 75 patients, treatment with Curcumin (CUC-01, yellow solution), 300mg i.v. plus i.v. Paclitaxel (colorless solution) 80 mg /m2 BS i.e., once weekly for 12 weeks.
Group B, 75 patients, treatment with Paclitaxel (colorless solution) 80 mg /m2 BS, i.v. plus placebo i.v. solution (250 ml, yellow solution for masking/blinding), once weekly for 12 weeks.
Primary objective of the study:
To assess:
Secondary objectives of the study:
To assess:
Full description
RATIONALE
Various preclinical, clinical, and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic, as a mediator of chemoresistance, chemopreventive, and as a therapeutic agent. However, the main problem associated with the use of curcumin in humans is its low absorption from the gastrointestinal tract, poor solubility in body fluids and low bioavailability. To overcome the pharmacokinetic and bioavailability limitations of oral administration, water soluble curcumin, Curcumin® (CUC-01) injection, a clear, yellow viscous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion was elaborated. Curcumin® (CUC-01) injection is patented pharmacy product and sold per individual prescription in Germany and other countries for Cancer Centers. However, clinical efficacy and safety of these formulation have to be confirmed in this study.
Development of multidrug resistance (MDR) against a variety of conventional and novel chemotherapeutic agents is a significant challenge in effective cancer therapy. Paclitaxel, one of the most prescribed conventional chemotherapeutic agents, acts as microtubule stabilizer and blocks cancer cells in the G2/M phase, thus preventing them from mitosis. It is also an apoptosis inducer in cancer cells. However, one of the main drawbacks of its use is that it is also a substrate of P-gp and treatment with PCL induces the overexpression of the efflux pump in the cancer cells. NF-κB is a transcription factor that controls the expression of genes involved in a number of physiological responses including differentiation, inflammation, apoptosis and upregulation of the P-gp. The PI3K/Akt pathway is also another over-activated pathway in a wide range of tumor types and therefore its over-activation leads to increased cancer-cell survival, proliferation, and growth and it also promotes NF-κB activity, all affects the success of the chemotherapy with Paclitaxel. Curcumin is known to downregulate both the PI3K/Akt and NF-κB pathways independent of each other, and thus it can act as a mediator of chemoresistance by sensitizing cancer cells to a conventional chemotherapeutic agents.
It has been suggested that co-administration of Paclitaxel and curcumin will help to overcome multidrug resistance in cancer. Synergistic interaction of curcumin and paclitaxel was demonstrated in paclitaxel (Taxol)-resistant breast cancer cells, human breast cancer xenograft model, in MDA-MB-231 and MCF-7 human breast cancer cells and many other cancer cell lines. In vivo, this combination treatment produced a three-fold tumor inhibition with each of these cell lines. Furthermore, the combination of paclitaxel and curcumin exerted increased anti-tumor efficacy on mouse models These results clearly indicate combination of Curcumin with paclitaxel could have significant clinical advantages for the treatment of breast cancer.
Curcumin exerted in vitro anti-breast cancer activities through regulation of matrix metalloproteinase (MMP)-2, B-cell lymphoma 2 (Bcl-2), Bax, flap endonuclease 1 (Fen1), NF-E2-related factor 2 (Nrf-2) factors, and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling.
Therefore, and based on this evaluation, we intend examining the effect of Curcumin ®, (CUC-01) in advanced and metastatic breast cancer in this randomized, double-blind, placebo-controlled study.
STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, two arms parallel group phase 2 study:
Group A, 75 patients, treatment with Curcumin (CUC-01, yellow solution), 300mg i.v. plus i.v. Paclitaxel (colorless solution) 80 mg /m2 BS i.e., once weekly for 12 weeks.
Group B, 75 patients, treatment with Paclitaxel (colorless solution) 80 mg /m2 BS, i.v. plus placebo i.v. solution (250 ml, yellow solution for masking/blinding), once weekly for 12 weeks.
Therapy schedule weekly:
PRIMARY OBJECTIVE
To assess:
SECONDARY OBJECTIVES
To assess:
NUMBER OF SUBJECTS
150
TEST PRODUCT, DOSE, AND ROUTE OF ADMINISTRATION
Curcumin® (CUC-01) injection, BRIU GmbH at dose 300 mg. Each vial contains 20 ml of the concentrate (concentration of Curcumin - 15 mg/ml) containing in total of 300 mg of Curcumin, which has to be diluted in 250 ml of physiological solution (0.9% NaCl) before use, total volume - 270 ml of infusion solution.
Investigational Active Ingredients: Curcuminoids (syn: Curcumin, isolated from turmeric rhizome Curcuma longa, Zingiberaceae.
CUC-01 will be administered intravenously (IV) once in every 7 days for 12 weeks.
Therapy schedule weekly:
CONTROL PRODUCT, DOSE AND ROUTE OF ADMINISTRATION
Placebo: Riboflavin solution which has strong yellow-orange color and visually is not distinguishable from Curcumin.
Placebo will be administered intravenously (IV) once in every 7 days for 12 weeks
Therapy schedule weekly:
EFFICACY EVALUATIONS.
Primary endpoint
Primary outcome measures:
Clinically, radiologically measurable disease, tumour markers:
Secondary endpoints.
Secondary outcome measures:
Safety Evaluations
Tolerability will be assessed by the nature and incidence of adverse events. Change in clinical safety labs from baseline to end of the study Incidence of adverse events, (CTCAE, v4.0≤).
STATISTICS
Statistical analysis will be performed on an intent-to-treat basis. Survival Analysis for time-to event endpoints.
Assessment of baseline characteristics - between groups comparison will be made by:
Analysis of changes within treatment groups in the course of the study (before versus after) was performed by:
Assessment of efficacy of study medications was achieved by between groups comparison of mean changes from the baseline (differences before and after treatment of every single patient) using:
Survival Analysis Statistical tools (Kaplan-Mayer analysis with log-rank test, Cox regression etc.) will be used for assessment of the TTP, PFS and TTTF.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Patients must fulfill all the following criteria to be eligible for this study.
Patient should be able to give fully informed written consent according to International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) guidelines and to comply with the instructions in the protocol.
Patients should be diagnosed with histologically-proven breast carcinoma.
Female subjects 18 years or older.
Radiographic evidence of measurable disease is required and must have been performed within 8 weeks prior to randomization. Acceptable studies include plain radiographs, ultrasound imaging, computed tomography scans and magnetic resonance imaging. Other studies may be acceptable with the approval of the principal investigator.
Bidimensionally measurable manifestations of progressive advanced disease after one prior chemotherapy regimen, or locally advanced or MBC that progressed during or within 12 months of completing an adjuvant or neoadjuvant chemotherapy regimen or other cases of breast cancer in which weekly paclitaxel treatment is considered an adequate approach.
No Herceptin treatment 4 weeks before and during the study.
No other chemotherapy and bisphosphonate therapy 4 weeks before random assignment and during the study. Prior and concomitant hormonal therapy is allowed.
Karnofsky performance score (KPS) ≥60, ECOG≤2.
Life expectancy 3 month or greater, as estimated by the responsible clinician.
Women of child-bearing age must use effective contraception.
Sufficient hematological status. Adequate bone marrow function defined as:
Adequate renal function: calculated creatinine clearance (Cockcroft-Gault formula) greater than 45 ml/min;
Adequate hepatic function defined as a total bilirubin less than Upper Limit of Normal (ULN), Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) less than 2.5 x ULN, or 1.5 x ULN if Alkaline Phosphatase (Alk Phos) less than 2.5 x ULN. Alk Phos less than 5 x ULN unless patient has bone metastases;
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
150 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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